The interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn. The stoichiometry of the heteroassemblies is well defined with an αSyn:huPrP molar ratio of about 1:1. The αSynO−huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of αSynO, residues 95−111 in the intrinsically disordered N-terminus, corresponds to the region required for αSynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of αSynO and Alzheimer’s disease-associated amyloid-β oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that αSynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies.

ion病毒蛋白（PrP）和α-突触核蛋白（αSyn）寡聚体的相互作用会引起突触损伤，可能触发帕金森氏病和其他突触核蛋白病。在这里，我们报告说，αSyn低聚物（αSynO）与人类PrP（huPrP）聚集成微米级的缩合物。缩合反应需要低聚物中的αSyn具有多价，因为单体αSyn并未观察到与huPrP发生簇聚。用约1：1的αSyn：huPrP摩尔比很好地定义了杂合体的化学计量。αSynO-huPrP相互作用具有高亲和力，这表示缓慢的解离。负责αSynO缩合的huPrP区域，即本征无序的N末端的残基95-111，对应于αSynO介导的认知障碍所需的区域。此外，HuPrP 实现了αSynO和阿尔茨海默氏病相关淀粉样β低聚物的共聚，从而提供了两个淀粉样蛋白通过相互连接的内在无序蛋白区域进行交叉相互作用的案例。结果表明，αSynO介导的huPrP缩合参与突触核蛋白病的发病机理。